Control of Bronco-Spasm in Family Practice

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Control of Bronco-Spasm in Family Practice - Beyond Inhalation Therapy Inhaled medications are the cornerstone of asthma/COPD therapy, but only be effective if used properly. The effect of particle size on the site of preferential deposition in airways Lung disease & Drug Deposition

. The degree of lung disease influences the pattern of drug deposition within the lungs. . Several studies have shown that central airway deposition is enhanced as mucus plugging, turbulent airflow & airway obstruction increase. . Therefore, in the face of severe lung disease, little or no drug may deposit in the lung peripheral airways.

Eur Respir J. 2011 Jun;37(6):1308-31. Lung disease & Drug Deposition

• This is important for corticosteroids.

• Corticosteroid receptors are also present throughout the airways and inflammation has been shown to exist in all regions of the lungs in asthma and COPD .

• For these reasons, uniform distribution of an ICS throughout the airways, following inhalation, may be preferable.

Eur Respir J. 2011 Jun;37(6):1308-31. Limitations of aerosol therapy

• Not all inhalation devices are appropriate for all patients • Based on a real-life setting, it has been reported that 76% of patients using a pMDI & 49–54% of those using a BA- pMDI make at least one error when using their inhaler. • In addition, between 4 and 94% of patients using a DPI do not use it correctly and • 25% have never received inhaler- technique training.

pMDI- Pressurized Metered Dose Inhaler, breath-actuated pMDIs (BA-pMDI), dry powder inhaler (DPI) Eur Respir J. 2011 Jun;37(6):1308-31. Patient Behaviour & Deposition • Studies have shown that a very high proportion of patients do not have the competence to use their device effectively, either because they have never been shown or because they have forgotten what they were taught. • In addition, many of those who are able to demonstrate a good technique in the clinic will Problem in the elderly contrive to use the device ineffectively in routine use. Limitations of aerosol therapy • Cold Freon effect : – The initial reaction to the cold blast of MDI propellant on the back of the throat

– Can often result in the patient aborting the inhalation process and hence receiving inconsistent delivery to the lungs.

Eur Respir Rev 2005; 14: 96, 102–108 Therapeutic Issues of Inhaler delivery devices

Metered Dose Inhaler More than 50% patients perform ≤ 5 out of 9 steps for correct use of inhaler

Failure to co-ordinate actuation with inhalation and to hold breadth after inhalation

Deposition of 50-80 percent of actuated dose in oropharynx

Dry Powder Inhaler Rapid inhalation promotes greater deposition in larger central airways

Restrepo RD et al. International Journal of COPD 2008:3(3) 371–384. Therapeutic Issues of Inhaler delivery devices

Spacer can prove to be bulky

Face mask reduces the delivery to lungs by 50% Nebulizer is bulky, expensive, time consuming and output is dependent on device and operating parameters

Restrepo RD et al. Medication adherence issues in patients treated for COPD. International Journal of COPD 2008:3(3) 371–384 Aerosol Delivery Devices. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. Available from: URL: http://www.ncbi.nlm.nih.gov/books/NBK7233/figure/A1472/?report=objectonly Myths Related to use of Inhalers

 Inhalers are habit forming

 Inhalers cause dryness of nose and mouth

 Inhalers affect the physical activities of a child

 Inhalers stunt the child growth

 Child becomes lethargy with the use of inhaler

Renaut V. Nursing and Midwifery Research Journal,. 2014; 10(1): 7 Adherence: A key Issue in Asthma & COPD

According to the WHO, for inhaled therapy to be effective, the patient must use a device effectively and adhere to a regular treatment regimen

Approximately 50% of adults & children on long- term therapy for asthma fail to take medications as directed at least part of the time.

Studies demonstrated: increased illness, exacerbations, visits to the emergency department, morbidity, & mortality in non-adherent asthma patients

Updated GINA 2015. Available from: URL: http://www.ginasthma.org/local/uploads/files/GINA_Report_2015.pdf Factors Involved in Non-Adherence

Medication Usage Non-Medication Factors

 Difficulties associated  Misunderstanding/lack of with inhalers information

 Complicated regimens  Inappropriate expectations  Fears about, or actual  Underestimation of severity side effects  Attitudes toward ill health  Cost of medication.  Cultural factors  Distance to pharmacies  Poor communication Poor -Adherence

Fears about, or Complicated actual side regimens effects Uncontrolled Asthma

Unable To Inhale Drug doesn't reach Drugs Reliably to peripheral Children & elderly airway Results into Uncontrolled Asthma/COPD

Curr Med Res Opin. 2008;24(12):3443-3452. What is the alternative for patients who are unable to inhale drugs reliably ? Circadian Rhythm & Asthma Night-time: an Asthmatic's version of a perfect storm

 Bronchial asthma is a disease based on established circadian rhythm.

 Anti-inflammatory: Cortisol & Epinephrine reach a nadir during the night.

 Pro-inflammatory: Histamine & melatonin levels spike, increasing inflammation.

 Genetic component further exacerbates symptoms.

 “The pituitary gland tells the adrenal gland to produce cortisol, but there is a blunting of this response in nocturnal asthma.”

J Control Release. 2012 Nov 10;163(3):353-60 Chronopharmacology: The Right Formulation At The Right Time

 The symptoms of asthma worsen during midnight to early morning & therefore it is required to deliver the drug in such fashion that it will be effective during the time of asthma attacks.

 Chronotherapy : drug delivery at a specific time as per the patho- physiological need of the disease, to improve patient compliance. Adv Drug Deliv Rev. 2010 Jul 31;62(9-10):946-55. PREREQUISITES OF THERAPEUTIC AGENTS FOR THE TREATMENT OF CHRONIC RESPIRATORY DISEASES

1. TREATMENT ADHERENCE: Very important in management of chronic respiratory diseases. INHALED DRUGS: • Often Associated With Low Treatment Adherence. • Difficulty In Mastering The Technique For Using Inhalers • Insufficient inhalation rate. 2. NO DRUG TOLERANCE OVER LONG TERM USE 3. DRUG RESERVOIR-CONSISTENT DRUG DELIVERY: For 24 hour efficacy 4. UNDISTURBED SLEEP: Burioka et al. assessed the effects of tulobuterol on the expression of the human clock gene Per1 mRNA and confirmed that the drug does not affect its expression. implying that tulobuterol at bedtime does not affect night sleep.

Burioka N, Takata M, Endo M et al. Treatment with beta2-adrenoceptor agonist in vivo induces human clock gene, Per1, mRNA expression in peripheral blood. Chronobiol Int 2007;24:183-9. Tulobuterol Patch Formulation

 Tulobuterol Patch:

 Designed in accordance with the concept of chronotherapy

 The plasma drug concentration is controlled in such a manner that it is highest during early morning, when the respiratory functions are most severely suppressed.

 This controlled release helps to reduce the systemic adverse reactions associated with excessive drug concentrations in the blood.

Allergol Int. 2012 Jun;61(2):219-29. Developmental Rationale of Tuloplast

Allergol Int. 2012 Jun;61(2):219-29. “Tulobuterol patch” A Unique Transdermal Delivery System

CRYSTAL RESERVOIR TECHNOLOGY: The tulobuterol patch delivery system prepared using crystal reservoir technology. MORNING DIPS WELL CONTROLLED: It has been shown to significantly contribute to the pharmacotherapy of asthma by countering the morning dip in respiratory function. IMPROVED QOL: Since single Patch a day provides therapeutically effective drug concentration via the systemic circulation, in Asthma & COPD, it improves patients’ QOL. EXCELLENT TREATMENT ADHERENCE: Once-daily application makes Tulobuterol patch excellent in terms of treatment adherence and convenience. LONG TERM MANAGEMENT: Transdermal delivery provides consistent relief thus suitable for the long-term management of chronic respiratory diseases like Asthma & COPD. (No decrease in efficacy or tolerance observed with tulobuterol patch, even after year-long use.) Technology of Tuloplast Patch It is composed of three distinctive layers: 1) Backing film: The innermost layer of non-woven laminate & a polyester. Easily applied on the skin, causes minimal discomfort. creates minimum moisture, while contents are gradually transmitted to the skin.

2. Drug matrix: middle layer composed of polyisobutylene rubber. It has efficient rate of adhesion that can provide & sustain the effectiveness of the drug. It allows the content of the patch to penetrate in the skin layer. 3. Liner: The outermost layer. The surface of the liner is made of silicone & modified polyester. It protects the drug matrix & helps sustain the drug’s efficiency rate. Lengthen the therapeutic effect. Tuloplast Drug Matrix System

Allergol Int. 2012 Jun; 61(2):219-29. MAINTAINS SERUM CONCENTRATION WITHIN THERAPEUTIC RANGE FOR 24 HOURS Pharmacokinetics of Tuloplast

TULOBUTEROL PATCH 2 mg

Standardized preparation (adhesive skin patch 2 mg)

)

Plasma concentration of concentration Plasma TULOBUTEROL ( TULOBUTEROL

Detachment

Time after application (hr)

Analysis of pharmacokinetic parameters confirmed bioequivalence for both drugs Pharmacokinetics

Dose Cmax Tmax T1/2 AUC0-48hr (No. of Drug administered (ng/mL) (hr) (hr) (ng•hr/mL) cases)

Tulobuterol Patch 0.5 mg 0.48 ± 0.22 11.4 ± 4.1 11.1 ± 4.4 10.75 ± 7.65 0.5 mg [n=23] Standardized preparation (adhesive skin patch 0.42 ± 0.20 15.4 ± 5.0 10.6 ± 4.2 10.67 ± 7.26 0.5 mg)

Tulobuterol Patch 1 mg 0.59 ± 0.32 9.1 ± 2.1 10.4 ± 1.9 11.09 ± 6.86 1 mg [n=24] Standardized preparation (adhesive skin patch 0.56 ± 0.27 11.5 ± 3.7 9.7 ± 1.3 12.10 ± 7.35 1 mg)

Tulobuterol Patch 2 mg 1.29 ± 0.60 11.0 ± 2.7 11.0 ± 3.4 27.62 ± 18.77 2 mg [n=24] Standardized preparation (adhesive skin patch 1.24 ± 0.63 14.5 ± 4.5 10.0 ± 4.5 29.65 ± 20.62 2 mg) Tulobuterol Plasma Concentration Curve Patch versus oral tablets

Effective Concentration

Allergology International Vol 61, No2, 2012 Tulobuterol Patch Long Term Effect on PEF

Increase in the morning PEF values after treatment with 1 mg or 2mg tulobuterol patch. **p < 0.01, p < 0.05.

Place of Tuloplast in Asthma Therapy: GINA 2015

Adults, adolescents and children 6-11 years

First Add-on Controllers

•Updated GINA 2015. Available from: URL: http://www.ginasthma.org/local/uploads/files/GINA_Report_2015.pdf Place of Tuloplast in Pediatric Asthma Therapy: Japanese Guidelines 2014

Use of LABA is recommended to be used from Step 3 onwards Tulobuterol patch specifically mentioned to be used in children less than 2 years of age

Classified as LABA

Hamasaki Y et al. Japanese guidelines for Childhood Asthma 2014. Allergology International 2014. 63: 235-56 GOLD 2015

•Updated GOLD 2015. Available from URL: http://www.goldcopd.org/uploads/users/files/GOLD_Report_2015_Apr2.pdf Place of Tuloplast in COPD Therapy: GOLD 2015

•Updated GOLD 2015. Available from URL: http://www.goldcopd.org/uploads/users/files/GOLD_Report_2015_Apr2.pdf Clinical Evidence In Pediatric patients Tulobuterol patch versus oral salbutamol sulfate in Childhood Asthma

Methods:  92 children with mild and moderate acute asthmatic attack were randomly assigned to receive either Tulobuterol patch or oral salbutamol  Both groups received routine treatment with antihistamine, selective leukotriene receptor antagonist and glucocorticoid  Duration of the treatment-14 days Results:  The Tulobuterol group had significantly lower symptom scores than the salbutamol group on third day of treatment  On the fourteenth day of treatment, the Tulobuterol group had a significantly lower cough score than the salbutamol group

Conclusion:  Compared with oral salbutamol sulfate, Tulobuterol patch has a better therapeutic efficacy and a higher safety in children with mild or moderate acute asthmatic attack

Lin Q, Liu QH, Bao YX. Zhongguo Dang Dai Er Ke Za Zhi. 2013 ;15(6):462-5 The Use of Patch Formulation of Tulobuterol (LABA) In The Treatment of Severe Pediatric Asthma

• Tulobuterol patch with ICS vs. Inhaled salmeterol plus ICS • Randomized, prospective

Yoshihara S. Ann Allergy Asthma Immunol. 2006 Jun;96(6):879-80. Conclusion: • In 18 pediatric patients it was found that adding tulobuterol patch to ICS resulted in significantly greater improvement in the PEF values and a significantly higher percentage of respiratory symptom-free days than increasing the dose of ICS

• Tulobuterol patch useful for the long-term management of asthma in the pediatric population

• The Tulobuterol patch & ICS combination significantly improved the quality of life, in a similar manner to the salmeterol inhalant, by controlling pulmonary functions and respiratory symptoms superior to increasing the dose of ICSs.

Yoshihara S. Ann Allergy Asthma Immunol. 2006 Jun;96(6):879-80. Tulobuterol patch plus LTRA vs. Oral Sustained release Theophylline plus LTRA

• Multicenter, Randomized, open label

• Duration-4 weeks, n=64

• Children(4-12 years) with pediatric asthma on long term LTRA therapy

• Results:

– Thirty-three and 31 patients were treated with tulobuterol patches and theophylline, respectively.

– % PEF measured in the morning and before bedtime was significantly higher at all times in the treatment period compared with baseline in the tulobuterol patch group (p < 0.001), and was significantly higher in the tulobuterol patch group compared with the theophylline group.

– FeNO was similar and unchanged from baseline in both groups.

– There were no drug-related adverse events in either group.

Katsunuma T. Allergol Int. 2013 Mar;62(1):37-43. •Tulobuterol patch elicited significantly greater improvements in % PEF measured in the morning & before bedtime compared with sustained-release theophylline in children on long-term LTRA therapy. •Effects were observed without worsening of Fractional Exhaled Nitric Oxide (FeNO) indicating that it does not exacerbate airway inflammation in children. •Short-term continuous use of a transdermal β2 agonist is an effective therapy for pediatric asthma without inducing airway inflammation. Katsunuma T. Allergol Int. 2013 Mar;62(1):37-43. Tulobuterol patch for acute asthma exacerbations in young children

• Tulobuterol patch (TP) Vs. Placebo patch • Randomized, multicenter, double-blind, placebo-controlled • 1 year duration, n=86 • Children aged 0.5-3 yrs old with mild-to-moderate persistent asthma • The time to symptom resolution was significantly shorter (p = 0.001) and the total respiratory symptom score (p =0.0457) was significantly lower in the TP group than in the placebo group. • In young children with mild to-moderate asthma who had been treated with anti-inflammatory drugs, using the TP soon after the appearance of URTI symptoms led to quicker resolution of respiratory symptoms and lower respiratory symptom scores.

Katsunuma T. Allergy Asthma Proc. 2012 May-Jun;33(3):e28-34. Usefulness of Tulobuterol patch in the long-term management of childhood asthma

• Assessed the effect of adding the Tulobuterol patch in severe childhood asthma cases in which morning dipping was observed despite treatment with a high- dose beclomethasone dipropionate (BDP) 800 μg. • The results showed that adding Tulobuterol patch daily at 8:00 pm improved the asthma attack points & morning PEFR (p<0.05, n=9) significantly > BDP (1200 μg) alone. • Early improvement was observed, within several days, & the inhibition of morning dipping lasted until 12 wks later. • Based on the results of this study the Tulobuterol patch has an additive effect with steroid inhalants, & it can be used in all age groups, including infants. • Compliance is also good because of its convenience, & there are fewer side effects than with oral LABA. • These findings suggest that this Tulobuterol patch is highly useful as a drug for the long-term management of childhood asthma. Yoshihara, S. et al. Journal of Allergy and Clinical Immunology , Volume 113 , Issue 2 , S33. Tulobuterol tape in children with cough variant asthma

• 106 patients with cough variant asthma (CVA), randomly divided into 2 groups. Both received inhaled corticosteroids, • Treatment group -Tulobuterol patches. Control group - Procaterol hydrochloride tablets. • Results: – For the Tulobuterol group, the symptom of cough was obviously alleviated. The time for relieving cough was significantly shorter than that in control group (P<0.05). – After the course of 2 weeks, the effective rate of treatment group & control group were 90.4% and 79.6%, respectively. There was significant difference between the 2 groups. (P<0.05). – After treatment, the FEV1 & PEF of treatment group were both improved significantly as compared with control group (P<0.05). – There was no significant difference between the Tulobuterol patches & the procaterol hydrochloride tablets in relieving airway hyperactivity (P<0.05). – The Tulobuterol patches had low adverse reaction rates & good compliance. • Conclusions: The Tulobuterol patches show dramatic effect on CVA in children. It has a

good compliance, safe and effective. WEI Bing . Journal of Applied Clinical Pediatrics. 2011-09 Tulobuterol tape in children with cough variant asthma • 100 children with mild to moderate cough variant asthma randomly divided into experimental & control group. • Antihistamine & selective leukotrienes receptor antagonist were given in both groups. • In addition, the experimental group -Tulobuterol tape at bedtime. Results: – After 14 days, the symptom scores were significantly decreased in experimental group than that in control group; the percentage of improvement in total symptom score was significantly different between two groups(P <0.05),Tulobuterol achieved clinical control. – There was no significant difference in PEF scores between the 2 groups (P <0.05). Conclusions: Tulobuterol tape is effective and safe for treatment of mild to moderate cough variant asthma. Chu Yi. Journal of Clinical Pediatrics. 2012-02. Effects of Tulobuterol Patches on Bronchiolitis in Infants

• Compared Tulobuterol patches & nebulized salbutamol on bronchiolitis in infants.

• 60 infants with bronchiohtis were randomly divided into observation group (Tulobuterol patches ) & control group. Duration-7 days treatment

• Tulobuterol patches group was given combined with nebulization ipratropium bromide & budesonide, whereas the control group was given inhalation of salbutamol, ipratropium bromide & budesonide.

• Results:

– Nocturnal sleep was improved significantly in observation group (Z =1.974，P < 0.05).

– The tidal volume, TI/TE, TPTEF/TE and VPEF/VE were significantly improved after 7-d treatment in both groups (P < 0.05), but no significant differences were found on the first day of treatment between two groups (P > 0.05).

– The values of TPTEF/TE and VPEF/VE were significantly better in observation group than those in control group after 7-d treatment (P < 0.05).

• Conclusion: Tulobuterol patches combined with nebulized ipratropium bromide and budesonide have a certain effect in treatment of bronchiohtis in infants showing faster effect, fewer adverse reactions and good compliance．

WANG Yanli,LU Xiaoxia,WANG Ying, et al. Effect of Tulobuterol Patches on Infant Bronchiolitis[J]. , 2013, 41(6): 569-571 . Tulobuterol tape in treatment of recurrent wheezing in infants & young children

• 62 infants & young children with recurrent wheezing randomly divided into treatment group(n=31) & control group (n=31). • When wheezing was relieved, patients in treatment group were treated with budesonide suspension fluid inhalation combined with Tulobuterol tape for 12 wks, while those in control group were treated with budesonide suspension fluid inhalation only. • Patients were followed up during the 2nd,4th,6th,8th,10th and 12th wk. • Results: Thirty patients in treatment group and 29 patients in control group completed the treatment and follow up. • The scoring of cough, frequency of wheezing, scoring of wheezing and scoring of combination use of drugs in treatment group were significantly lower than those in control group (P-0.01),& the frequency of respiratory tract infection in treatment group was significantly lower than that in control group(P-0.05).

Conclusion: Budesonide suspension fluid inhalation combined with Tulobuterol tape is more effective and safe

than budesonide suspension fluid inhalation only in treatment of recurrent wheezing in infants and young children.

ZHU Yaju. Journal of Shanghai Jiaotong University(Medical Science) 2011-12. The clinical effects and nursing of 50 infantile asthma patients treated with Tulobuterol patch

• Objective: To investigate the clinical effects and nursing of infantile asthma patients treated with Tulobuterol patch. • Methods: 96 infantile asthma patients were randomly divided into two groups, control group,46 patients were given combined therapy (anti-infective, antivirus, antitussive, expectorant, etc) and routine care; treatment group,50 patients in addition to the above addressed management, plus were given Tulobuterol patch (Amiaid patch) 0.5mg percutaneously before sleeping, and proper nursing, the clinical effects of the two groups were observed. • Results: The clinical effects of the treatment group (cough, asthma, wheezing, wet rales were disappeared)were significantly better than the control group, the clinical effects of the two groups were significantly difference(P=0.0006),after statistical processing. • Conclusion: Tulobuterol patch has a remarkable effects on infantile asthma, it could shorten the course. Tulobuterol patch is safe and effective for infantile asthma without adverse drug reactions,and had the same clinical efficacy as terbutaline inhalation.

LI Jian. Practical Clinical Medicine. 2012-11 Tulobuterol Inhibits Rhinovirus infection

• Tulobuterol patch has been designed to yield sustained β-2 agonistic effects & has been used as LABA in Japan. • LABAs reduce the frequency of exacerbations of bronchial asthma. However, inhibitory effects of LABAs on the replication of rhinovirus (RV), the major cause of exacerbations, have not been demonstrated. • To examine the effects of Tulobuterol on RV replication and on the production of the replication- induced pro-inflammatory cytokines, human tracheal epithelial cells were infected with a major group RV, type 14 rhinovirus (RV14). Tulobuterol reduced the RV14 titers and RNA levels; the concentrations of cytokines, including interleukin (IL)-1b, IL-6, and IL-8, in the supernatants; and susceptibility to RV14 infection. Tulobuterol reduced the expression of intercellular adhesion molecule-1 (ICAM-1), the receptor for RV14, and the number of acidic endosomes in the cells in which RV14 RNA enters the cytoplasm. • Tulobuterol inhibited the activation of nuclear factor kappa B (NF-jB) proteins in nuclear extracts. A selective β2-adrenergic receptor antagonist, ICI 118551 [erythro-dl-1-(7- methylindan-4-yloxy)-3-isopropylaminobutan-2-ol], reversed the inhibitory effects of tulobuterol on the RV14 titers and RNA levels, the susceptibility to RV14 infection, cytokine production, and ICAM-1 expression. • Tulobuterol may inhibit RV replication by reducing ICAM-1 expression and acidic endosomes and modulate airway inflammation during RV replication.

Yamaya M, Physiol Rep. 2013 Aug;1(3):e00041. Tulobuterol PHARMACOLOGICAL STUDIES SUPPORTING THE CLINICAL RESULTS

1. PROMOTES CILIARY MOVEMENTS: One such study demonstrated that tulobuterol promotes airway ciliary movement, thereby enhancing airway clearance. This effect may improve expectoration and cough, which are the subjective symptoms of COPD. 1 2. IMPROVED CONTRACTILITY OF DIAPHRAGMATIC MUSCLES: COPD patients have low flat diaphragms, and the consequent decrease in the contractility of the respiratory muscles may be associated with decreased respiratory functions and subjective symptoms in patients with COPD. Shindoh et al.,2,3 reported the significance of the systemic effects of the tulobuterol patch. They also found that the increased contractility of diaphragmatic muscle was maintained for 24 h after the application of the tulobuterol patch and that the patch suppressed the decrease in the contractility of the diaphragmatic muscle for 24 h observed in a mouse model of endotoxin-induced sepsis. Suggesting, tulobuterol patch may increase the contractility of the weakened diaphragmatic muscle in both asthma and COPD patients.

1. Matthys H, et al. Action of tulobuterol and fenoterol on the mucociliary clearance. Respiration 1987;51:105-12. 2. Shindoh C, et al. Transdermal treatment with tulobuterol increases isometric contractile properties of diaphragm muscle in mice. Tohoku J Exp Med 2007;212:309-17. 3. Shindoh C, et al. Tulobuterol patch maintains diaphragm muscle contractility for over twenty-four hours in a mouse model of sepsis. Tohoku J Exp Med 2009;218:271-8. Other Clinical Studies in children SN Author year Test drug Study Design Duration N Patients Conclusion of the treatment 1 Suxiang Z et al. Tulobuterol Randomized,p 5-7days 96 Children 1. Total effective rate of the treatment group was 2006. patch rospective with 93.75%(45/48),while the control group was (treatment bronchiolitis 79.17%(38/48),there was significant difference group) vs between two groups control group. 2. Time to disappearance of signs & symptoms; chest X-ray recovery time and total course of disease was significantly shorter in treatment group 3. The clinical effect of transdermal Tulobuterol Patches in treating children with bronchiolitis is exact,usage is convenient,compliance is high,and there are no obvious adverse reactions.[16] 2 Yi Chu et al. TP plus Randomized,p 14 days 100 Children 1. After 14 days,the symptom scores were Antihistaminic rospective with mild to significantly decreased in experimental group s plus LTRA moderate than that in control group (Experimental) cough 2. Tulobuterol tape is effective and safe for vs variant treatment of mild to moderate cough variant Antihistaminic asthma asthma.[17] s plus LTRA(control)

3 Ya Ju ZHU et Budesonide Randomized,p 12 weeks 62 Recurrent 1. The scoring of cough, frequency of wheezing, al. 2006 suspension rospective wheezing scoring of wheezing was significantly lower than fluid inhalation those in control group plus plus 2. The frequency of respiratory tract infection in tulobuterol treatment group was significantly lower than that tape vs in control group[18] Budesonide suspension alone Jian LI et al Conventional Randomized,p 5 days 60 Asthma 1. Tulobuterol patch is safe and effective for infantile Treatment both rospective asthma without adverse drug reactions,and had the groups. same clinical efficacy as terbutaline inhalation[20] Tulobuterol patch vs Terbutaline sulfate inhalation

Yanhua XI et al. Basic treatment Randomized,p 7 days 150 Pediatric 1. The clinical cure rate was 80% in treatment group plus rospective capillary while 20% in control group with no significant tulobuterol bronchitis difference from control group Patch 2. Tulobuterol patch has a definite therapeutic effect on (Treatment pediatric capillary bronchitis,and also has little side group) vs effect and excellent medication compliance.[22] Basic treatment plus terbutaline aerosol inhalation(cont rol group)

Genglian Z et al. Conventional Randomized,p 3-7 days 52 Bronchiolitis 1. Effective rate of treatment group was 84.62%,which treatment plus rospective was more than effective rate of control group(53.5%) Inhaled 2. Tulobuterol patch in adjuvant treatment of albuterol and bronchiolitis has obvious curative effect[23] iptatropium vs Conventional treatment with tulobuterol patch Clinical Studies in Adult Asthma Patients Transdermal Tulobuterol Added to Inhaled Corticosteroids in Asthma

Study Design: Randomized, double-blind, double-dummy, parallel-group, multicenter trial

Methods: Asthma patients requiring Inhaled SABAs despite treatment with ICS were randomized to receive tulobuterol tape 1 mg or 2 mg and corresponding placebo tape for 4 weeks (n=239)

Results: In both groups, daytime and night-time supplemental use of β2-agonists significantly decreased from baseline The number of rescue-free days and nights significantly increased from baseline in both groups

Tamura G et al. Allergology International. 2005;54:615-20 Transdermal Tulobuterol Added to ICS in Asthma Cont….

Increase in morning PEF and evening PEF after administration of tulobuterol patch **Significant difference between the point and baseline (P＜ 0.01). †Significant difference between 1 mg treatment group (square) and 2 mg treatment group (circle) (P＜ 0.05)

Tulobuterol patch is a convenient and effective long-acting β2-agonist for the treatment of persistent asthma.

Tamura G et al. Effect of Transdermal Tulobuterol Added to Inhaled Corticosteroids in Asthma Patients. Allergology International. 2005;54:615-20 Effects of the Addition of Beta2-agonist Tulobuterol Patches to Inhaled Corticosteroid in Patients with Asthma

 24 Asthma patients on ICS were randomized to receive either ICS alone or ICS plus Tulobuterol patch (TP) for 4 weeks Results

Changes in % predicted value of morning peak expiratory flow (PEF) before to during the four-week treatment period in the tulobuterol patch and control group **p < 0.01 vs (Pre 2 and Pre1)

Percentage of sputum eosinophils decreased significantly from 12.7 ± 1.8% before treatment to 8.7 ± 0.9% after treatment

Hozawa S. Haruta Y, Terada M, Yamakido M. Effects of the addition of Beta2-agonist tulobuterol patches to inhaled corticosteroid in patients with asthma. Allergol Int. 2009 ;58(4):509-18 Effects of the Addition of Beta2-agonist Tulobuterol Patches to Inhaled Corticosteroid in Patients with Asthma

65 patients with asthma on ICS alone were randomized to receive additive treatments of either alone tulobuterol patch 2 mg/day (T) or pranlukast 450 mg/day(P) or oral slow release theophylline (SRT) 400 mg/day(U) for 4 weeks

Difference in %PEF from baseline to week 4 of treatment (∆%PEF)  1 of the 15 patients in the control(C) group 8 of the 17 patients in the pranlukast (P)group 7 of the 16 patients in SRT (U) group 13 of the 17 patients in the tulobuterol patch (T) group

FEV1 significantly increased after treatment with TP as compared totreatment with SRT or pranulukast TP can be used as a long-term add-on controller for patients with asthma receiving ICS Hozawa S. Haruta Y, Terada M, Yamakido M. Effects of the addition of Beta2-agonist tulobuterol patches to inhaled corticosteroid in patients with asthma. Allergol Int. 2009 ;58(4):509-18 Trial Summary: Adult Asthma

Author. Study groups Duratio N Study Findings year n Su N et al. Tulobuterol tape vs 233 4 Morning PEF, evening PEF, percentage 2007. Tulobuterol tablet weeks change significantly increased in tulobuterol vs tablet group The incidence of palpitations and tremor in the tulobuterol tape group was significantly lower than in the tablet group

Nishiyama Tulobuterol patch 54 4 The mean morning PEF and HRQoL score Q et al. 2 mg OD vs weeks were significantly improved in both groups 2006. Inhaled salmeterol The tulobuterol patch may be useful as a 50 mg BD controller medication in addition to ICS in moderate to severe asthma

Burioka N Transdermal 13 Application of the tulobuterol patch at et al. 2005. tulobuterol nighttime increased significantly the 03:00 h chronotherapy group average PEF and 24 h mean PEF Tulobuterol chronotherapy significantly increased both the level and stability of airway function over 24 hours Trial Summary: Adult Asthma

Author. Study groups Duratio N Study Findings year n Horiguchi T ICS and 1 year 24 PEF exhibited significant improvements at et al. 2004. tulobuterol 6 months and 1 year in patients treated with Transdermal or without inhalational steroids Thearpeutic One-year treatment with tulobuterol TTS System (TTS) did not appear to cause tachyphylaxis. OR Tulobuterol TTS is considered quite Tulobuterol TTS beneficial in improving quality of life (QOL) without ICS

Kume H . Tulobuterol patch 8 7 The early morning reduction in PEF rate 2002. 2 mg once daily weeks was suppressed with tulobuterol patch The rescue use of inhaled Beta- agonists and symptom scores underwent significant reduction

Kato H. Transdermal Review Tulobuterol TTS is superior as compared 2002. tulobuterol to oral formulations of Beta2 agonists in terms of pharmacokinetic profile and clinical trial efficacy Clinical Evidence In COPD Patients BAREC Study: Comparison between Tulobuterol Patch and inhaled Salmeterol in COPD Methods:  Multicenter, parallel-group, comparative study of the tulobuterol patch and inhaled salmeterol in 92 patients with stable COPD Results:  Improvements in the morning and evening PEF values in both groups, with no significant intergroup difference

 Both groups demonstrated significant improvement in FEV1 , FVC , PEF  Significantly greater improvement of the St. George Respiratory Questionnaire (SGRQ) at 8 weeks after the start of treatment was observed in the tulobuterol patch group compared with the salmeterol group  Treatment compliance was also significantly better in the tulobuterol patch group than in the salmeterol group Once daily transdermal tulobuterol is as effective or better than inhaled salmeterol in the management of stable COPD, with significant effects on quality of life

Fukuchi Y et al. Clinical efficacy and safety of transdermal tulobuterol in the treatment of stable COPD: an open-label comparison with inhaled salmeterol. Treat Respir Med. 2005;4(6):447-55 Superiority over Inhaled Salmeterol

Methods:  165 elderly patients with moderate to severe AECOPD were randomized to receive either tulobuterol patch 2 mg/day plus fluticasone propionate 250 micro g BD or Inhaled salmeterol/fluticasone 50/250 micro g BD

Results:  Significant improvement in TP group as compared to inhaled salmeterol in terms of:

• FEV1, PEF, 6 min walking distance and symptom scores • Frequencies of rescue medication, waking-up suffocating at night and days of hospital stay

Conclusion:  Tulobuterol patch is an effective and safe medication for the treatment of acute exacerbation of AECOPD

Yu-guang LI et al., Chinese Journal of Geriatrics;. 2012; 31(8): 679-82 “Tulobuterol Patch” Vs “Inhaled Salmeterol” In Stable COPD

Morning PEF Improvement over 12-week treatment period with Tulobuterol Patch and inhaled salmeterol in Stable COPD “Tulobuterol Patch” Vs “Inhaled Salmeterol” In Stable COPD

Evening PEF Improvement over 12-week treatment period with Tulobuterol Patch and inhaled salmeterol in Stable COPD “Tulobuterol Patch” Vs “Inhaled Salmeterol” In Stable COPD

St George’s Respiratory Questionnaire score during 12 weeks of treatment with tulobuterol patch and inhaled salmeterol in stable COPD. *p < 0.05, p < 0.05 (Intergroup). Adherence to prescribed medication in Asthma and COPD “As directed by physicians” Better treatment adherence to a transdermal tulobuterol patch than inhaled Salmeterol in COPD

Methods:  44 treatment-naïve elderly COPD patients were randomized to receive either tulobuterol patch 2 mg once daily or inhaled Salmeterol

Results:  The overall adherence rate was 90.3 ± 1.6% for TP and 75.5 ± 2.9% for salmeterol  6 minute walking distance and Quality of Life were significantly increased from baseline in TP group but not in salmeterol group

Conclusion:  Adherence levels were higher overall with TP than with inhaled salmeterol, and more stable across age groups and Mini-Mental State Examination (MMSE) levels Tulobuterol PHARMACOLOGICAL STUDIES SUPPORTING THE CLINICAL RESULTS

Methods:  13 COPD patients were treated with 2 mg transdermal tulobuterol once daily for 4 weeks

Results:  The maximum Borg scale for dyspnea and the Borg scale slope (BSS) decreased significantly from baseline to the end of treatment  The threshold load of dyspnea (TLD) increased slightly in the constant load test  No significant difference in blood pressure and heart rate 4 weeks after administration of tulobuterol patch compared to baseline

Conclusion:  Tulobuterol patch lead to significant improvement in self-assessed dyspnoea which may encourage patients to perform daily life activities or regular physical activity

Ichikawa M et al. J Thorac Dis. 2015 Apr;7(4):687-96. BAREC study “Tulobuterol patch”

With Tulobuterol patch, Drug reaches the peripheral airways through the systemic circulation after transdermal absorption, thereby maintaining “patency of peripheral airways” resulting in: 1.More effective expiration 2.Reduction of the residual volume. 3.Prevents pulmonary hyperinflation 4.Improves the exercise tolerance 5.Improves the patients’ QOL. Fukuchi Y, Nagai A, Seyama K et al. Clinical efficacy and safety of transdermal tulobuterol in the treatment of stable COPD: an open-label comparison with inhaled salmeterol. Treat Respir Med 2005;4:447-55. BAREC II Study: Additive effects of transdermal tulobuterol to inhaled tiotropium in patients with COPD

Methods: 103 patients with stable COPD were randomized to receive either inhaled tiotropium alone (Tio group) or both tulobuterol patch and inhaled tiotropium (Tio + Tulo group)

Results: In both groups, FEV1, FVC and dyspnea improved significantly after 8 weeks

Significant Percentage change in Inspiratory Capacity and significant improvement in SGRQ score was observed only in Tio plus Tulo group

Ichinose M et al. Beta-2 Agonist Research and Evaluation Committee in COPD (BAREC) Study Group. Additive effects of transdermal tulobuterol to inhaled tiotropium in patients with COPD. Respir Med. 2010 ;104(2):267-74 BAREC II Study: Additive effects of transdermal tulobuterol to inhaled tiotropium in patients with COPD

Effect of tulobuterol used in combination therapy on (A) morning and (B) evening peak expiratory flow (PF). *P < 0.05, **P < 0.01 (Tio group versus Tio plus Tulo group)

Additional administration of transdermal tulobuterol to inhaled Tiotropium in COPD produced significant benefits in dyspnea , SGRQ score and Pulmonary function without an increase in risk of adverse effects

Ichinose M et al. Beta-2 Agonist Research and Evaluation Committee in COPD (BAREC) Study Group. Additive effects of transdermal tulobuterol to inhaled tiotropium in patients with COPD. Respir Med. 2010 ;104(2):267-74 BAREC II study “Tulobuterol patch” as an add on to Tiotropium

• Tiotropium exerts its effects via muscarinic “M3 receptors”, while tulobuterol acts via the “β2 adrenergic receptors”. • Activated muscarinic M3 receptors are found mainly in the “central airways”, thus Tiotropium affects central airways rather than the peripheral airways. • Tulobuterol activates the β2 adrenergic receptors in the peripheral airways via the systemic circulation

The combination of the two agents have complementary effects and improve the functions of both the peripheral and central airways.

• Barnes PJ. Neural control of human airways in health and disease. Am Rev Respir Dis 1986;134:1289-314. • Ichinose M, Seyama K, Nishimura M et al. Additive effects of transdermal tulobuterol to inhaled tiotropium inpatients with COPD. Respir Med 2010;104:267-74. Snapshot of Indian Evidence

104 patients Asthma/COPD

Tulobuterol patch Salmeterol 2 mg OD 50 micro g/inhalation BD

Better improvement of morning PEF was found with Tulobuterol Patch compared to Salmeterol inhalation SGRQ score improved from baseline in TP group Compliance was better in TP as compared to inhaled salmeterol group No technical complaints

Once daily transdermal Tulobuterol patch is as effective or better than the inhaled long-acting beta2 agonist Salmeterol in the management of moderate to severe asthma/COPD, with significant effect on quality of life

Data on File Trial Summary: COPD

Author. Study groups Duratio N Study Findings Year n Abe T et al. Inhaled Tiotropium 4 16 Tio plus Tulo was associated with 2011. plus TP (Tio plus weeks significantly greater improvements than Tio Tulo) vs each in Impulse Oscillaion (IOS)-assessed Inhaled Tiotropium treatme markers of resistance (R5 and R5-R20), alone (Tio) nt reactance and reactance area, from (Crosso baseline to week 4) ver) Tio plus Tulo significantly improved dyspnoea and SGRQ score from baseline as compared to Tio alone Minami S Transdermal 4 16 Patients receiving TP exhibited significant et al. 2007. tulobuterol patch weeks improvement in the number and ease of (TP) Vs each sputum expectorations, cough frequency SRT treatme score, wheezing severity score and SGRQ nt score compared with baseline (Crosso Treatment of COPD patients with TP is ver) more effective than with theophylline Tulobuterol Patch: Clinically well Proven Adherence  Internet based questionnaire study to evaluate treatment adherence and convenience in asthma & COPD (n=1470)

 52.7% patients with asthma took inhaled drugs as indicated as against 86% patients with TP

 54.7% patients with COPD took inhaled drugs as indicated as against 86.6% patients with TP

 79.3% with asthma and 73.2% of those with COPD described TP as “very easy to use” with corresponding percentages being 42.7% and 32.1% for inhalers

Tamura G, Ohta K. Adherence to treatment by patients with asthma or COPD: comparison between inhaled drugs and transdermal patch. Respir Med. 2007;101(9):1895–1902 INDICATIONS

For treatment of patients with Asthma and COPD DOSAGE AND ADMINISTRATION:

Once daily, apply the tape to chest, back, or upper arm as below dosage regimen. . Children 6 months to 3 years : 0.5 mg . Children 3 to 9 years : 1.0 mg . Adults & children -> 9 years: : 2.0 mg

• Most effective if applied in the evening or at bedtime. Sites Of Application of Tuloplast USE IN SPECIAL POPULATIONS

• Pregnancy – Tulobuterol may be applied to pregnant women or women who may be pregnant only when medical benefits outweigh the risk. – The safety of Tulobuterol in pregnancy has not been established. • Lactation – If Tulobuterol is applied to nursing mothers, breast feeding should be avoided. – Transfer of Tulobuterol into milk has been reported in animal studies. • Pediatric Use – The safety of Tulobuterol has not been established in infants less than 6 months of age. Precautions for Application

 Before applying Tuloplast, clean and dry the application site.

 Choose a new site each time to avoid cutaneous irritation.

 Place Tuloplast on an area that is out of reach of children who may peel it off.

 Tuloplast should not be used within the wound as animal studies (rat) showed an increase in the blood level when Tuloplast was applied on the compromised skin. Adverse Reactions

 Clinically significant adverse reactions  Anaphylactoid symptoms: if patient is hypersensitive.  Serious decrease in serum potassium level : reported with β2 agonist.

Incidence unknown Hypersensitivity Rash, pruritus, urticaria

Cardiovascular Palpitations, facial flushing, arrhythmia, tachycardia

Tremor, headache, insomnia, general feeling of malaise, dizziness, excitement, Neuropsychiatric numbness, muscle spasms, heat sensation, feeling of stiffness

Gastrointestinal Nausea and vomiting, loss of appetite, diarrhea, stomach discomfort

Hepatic AST (GOT) increased, ALT (GPT) rise hematologic Eosinophil count increased Application site pruritus, application site erythema, contact dermatitis, application site Dermatologic pain, application site discoloration

CK (CPK) increased, decrease in serum potassium levels, chest pain, edema, dry Other mouth, muscle pain

Caution: If any symptoms are observed, application of Tulobuterol should be discontinued Tuloplast: Summary

1. World's first bronchodilator to be available as long-acting transdermal patch. 2. A unique TDS prepared using Drug matrix technology, achieves continuous release for 24 hr. 3. Serum levels increases gradually & maintain a steady state level. 4. Tuloplast counters the morning dip in respiratory function. 5. Several clinical trials confirm the efficacy of the Tuloplast in patients with asthma & COPD. 6. Drug reaches the peripheral airways via the systemic circulation, is useful for the long-term management of COPD. 7. The safety of the tulobuterol patch in asthma or COPD has been well established. 8. Tuloplast adherence is far better than in those on inhaled drugs. 9. Only once-daily application: useful for long-term management of COPD. 10.Potential to become a first choice in treatment, especially for children & elderly patients who are unable to inhale drugs reliably. “Tulobuterol patch” A Unique Transdermal Delivery System